Gemcitabine in Combination With New Platinum Compounds: An Update

ABSTRACT: Combinations of gemcitabine (Gemzar) with cisplatin (Platinol)
are among the most active new chemotherapy regimens developed for advanced non-small-cell
lung cancer. Carboplatin (Paraplatin) is a platinum analog devoid of many of the
nonhematologic toxicities associated with cisplatin. Although few direct
comparisons have been made, when administered by area under the
concentration-time curve (AUC) dosing, carboplatin is probably equivalent to
cisplatin in advanced non-small-cell lung cancer and provides an improved
therapeutic index. Based on its favorable toxicity profile, carboplatin has
supplanted cisplatin for use in combination with paclitaxel in several different
tumor types. Initial trials combining gemcitabine and carboplatin using standard
days 1, 8, and 15 dosing of gemcitabine suggested that thrombocytopenia was
problematic. More recently, 21-day schedules in which gemcitabine is
administered only on days 1 and 8 have demonstrated both efficacy and improved
toxicity profiles. Here we review recent studies investigating gemcitabine plus
carboplatin and preliminary data regarding combinations of gemcitabine with the
new platinum analog oxaliplatin. [ONCOLOGY 15(Suppl 6):13-17, 2001]

A number of randomized trials
and meta-analyses have concluded that platinum-based therapy results in improved survival, symptom
control, and quality of life compared to patients receiving supportive care
alone. In a Cox multivariate analysis of approximately 2,300 cases of advanced
non-small-cell lung cancer treated on studies of the Southwest Oncology Group
(SWOG), platinum-based chemotherapy emerged as an independent predictive factor
for improved survival, along with performance status and female gender.[1] In
fact, randomized cooperative group studies have failed to demonstrate that
adding another chemotherapeutic agent or agents to cisplatin (Platinol) improves
survival compared to cisplatin alone.[2,3] However, this perspective is now
changing.

Recently, several new chemotherapeutic agents such as
gemcitabine (Gemzar), paclitaxel (Taxol), docetaxel (Taxotere), vinorelbine
(Navelbine), and irinotecan (CPT-11, Camptosar) have demonstrated considerable
single-agent activity in non-small-cell lung cancer. In randomized trials,
these new agents, in combination with platinum compounds, have demonstrated
improved response rates or survival compared to cisplatin alone or older
platinum-based combinations. Combinations of gemcitabine and cisplatin are
theoretically attractive due to preclinical synergism related in part to
inhibition of repair of platinum-induced DNA damage, and have proven to be among
the most active in clinical studies.

Gemcitabine and Cisplatin

The most common dose and schedule has been gemcitabine delivered
on days 1, 8, and 15, with cisplatin given on either days 1, 2, or 15 of a
28-day schedule. In a recent phase III trial by Sandler et al,[4] this 28-day
schedule of gemcitabine (1,000 mg/m2 on days 1, 8, and 15) plus cisplatin (100
mg/m2 on day 1) was compared to cisplatin alone in patients with advanced non-small-cell
lung cancer.[4] Both response rate (30% vs 11%) and median survival (9 vs 6
months) were increased in the combination arm. As in most studies using this
28-day schedule, thrombocytopenia was dose-limiting, commonly resulting in
omission of the day 15 gemcitabine dose (Table
1). Grade 4 thrombocytopenia
occurred in 28% of patients receiving the combination; 22% received platelet
transfusions. Similarly, in the phase III trial of Crino et al,[5] in which
gemcitabine was delivered on days 1, 8, and 15, and cisplatin was given on day
2, grade 4 thrombocytopenia was reported in 38% of patients, while 15% received
platelet transfusions.[5]

In contrast, the Spanish Lung Cancer Group[6] conducted a trial
of a 21-day schedule delivering gemcitabine at 1,250 mg/m2 on days 1 and 8 and
cisplatin at 100 mg/m2 on day 1. Grade 4 thrombocytopenia occurred in 16%, with
only 3% of patients requiring platelet transfusion.[6]

It is important to point out that regardless of incidence,
thrombocytopenia associated with gemcitabine and cisplatin regimens in these
studies rarely resulted in bleeding and was, therefore, of little clinical
significance. Nevertheless, this observed difference in thrombocytopenia between
28- and 21-day schedules of gemcitabine/cisplatin appears to be particularly
cogent when considering development of combinations of gemcitabine with
carboplatin.

Although there have been few direct comparisons of cisplatin-
and carboplatin (Paraplatin)-containing regimens in non-small-cell lung
cancer, available literature suggests that carboplatin is equally efficacious.
For example, in a European Organization for Research and Treatment of Cancer
(EORTC) trial reported by Klastersky et al, etoposide plus carboplatin resulted
in survival equivalent to etoposide plus cisplatin in the treatment of advanced
non-small-cell lung cancer.[7]

While early studies dosed carboplatin by body surface area, more
recent trials have administered carboplatin based on formulas derived from a
targeted area under the concentration-time curve (AUC), thus accounting for
differences in renal excretion. Although carboplatin offers an improved
therapeutic index, namely reduced nonhematologic toxicities, compared with
cisplatin, additive myelotoxicity may be problematic when combining carboplatin
with other myelosuppressive chemotherapeutic agents. In initial trials combining
a day 1, 8, and 15 schedule of gemcitabine with carboplatin, severe
thrombocytopenia was problematic, prompting some investigators to conclude that
this regimen was not feasible.[8]

More recently, alternative dose schedules have been employed.
One approach has been a 21-day schedule, with carboplatin administered on day 1
and gemcitabine on days 1 and 8. The rationale is that in 28-day schedules
combining gemcitabine with either cisplatin or carboplatin, thrombocytopenia
requires that the day-15 gemcitabine dose be omitted in over 50% of courses.

A recent trial by the Spanish Lung Cancer Group reported by
Carrato
et al[9] is particularly instructive in optimizing the dose and schedule of
gemcitabine/platinum combinations.
Patients with advanced non-small-cell lung cancer were treated with
gemcitabine at 1,000 mg/m2 and carboplatin, at an AUC of 5 mg/mL/min. In
sequential cohorts of patients, gemcitabine was administered either on days 1,
8, and 15 of a 28-day cycle or on days 1 and 8 of a 21-day cycle. While these
two schedules proved to be equally efficacious, hematologic toxicity, especially
severe thrombocytopenia, occurred much more frequently with the 28-day cycle
(61% vs 17%) (Table 2). This difference in toxicity was observed despite
achieving a greater delivered dose intensity with the 21-day cycle.

Similarly, a pilot study of sequential combination chemotherapy
by Edelman et al[10] at the University of California, Davis, used a 21-day
schedule with day 1 and 8 dosing of gemcitabine at 1,000 mg/m2 and carboplatin
at an AUC of 5.5 for three cycles prior to sequencing to single-agent
paclitaxel. The gemcitabine/carboplatin regimen was well tolerated, with nadir
thrombocytopenia occurring on day 15, a nontreatment day, and with recovery by
day 21 in the vast majority of patients (Figure
1).

Grade 4 thrombocytopenia was observed in 19% of patients,
without significant bleeding sequelae. This level of thrombocytopenia is
comparable to that seen in the 21-day regimens of gemcitabine/cisplatin[6] and
gemcitabine/carboplatin.[9] The overall response rate in the Edelman study was
31% (95% confidence interval [CI] = 13%-53%) and the median survival was 10
months.[10] Table 3 compares the level of grade 4 thrombocytopenia observed in
several studies investigating gemcitabine and carboplatin combinations. Based on
relative efficacy and toxicity, new trials investigating gemcitabine/platinum
combinations employing either cisplatin or carboplatin are using 21-day
schedules with gemcitabine dosing on days 1 and 8.

Figure 2 shows the study design for a recently completed
randomized phase II Southwest Oncology Group (SWOG) study (S9806) evaluating two
different sequential combination chemotherapy regimens in advanced non-small-cell
lung cancer. If the results prove to be encouraging, S9806 will provide the
rationale for testing sequential vs concurrent three-drug combinations, with the
objective of determining the relative therapeutic index of each approach.

To further evaluate the day-21 gemcitabine/carboplatin regimen
developed by Edelman et al,[10] a National Coalition Trial will directly compare
this regimen to paclitaxel/carboplatin and to the nonplatinum combination of
gemcitabine/paclitaxel (Figure 3). A proposed Cancer and Leukemia Group B
(CALGB) trial will compare the sequential regimen of gemcitabine/carboplatin
followed by weekly paclitaxel immediately to gemcitabine/carboplatin followed by
weekly paclitaxel at the time of progressive disease, to the "triplet"
of the three agents given concurrently (Figure
4).

Oxaliplatin is a novel platinum derivative with a
1,2-diaminocyclohexane (DACH) carrier ligand, providing several therapeutic
advantages over classic platinum compounds such as cisplatin and carboplatin.
Oxaliplatin appears to be more potent than cisplatin, requires fewer DNA adducts
to achieve equal levels of cytotoxicity, and is relatively non-cross-resistant.[12]
Oxaliplatin has demonstrated impressive clinical activity against a number of
tumor types, including malignancies where cisplatin has relatively little
activity, such as colorectal cancer.

In non-small-cell lung cancer, the initial phase II trial has
reported a 15% response rate.[13] Due to the unique synergism between
gemcitabine and platinum compounds, combinations of oxaliplatin and gemcitabine
are of particular interest. Based on proposed molecular mechanisms of
interaction, the substitution of oxaliplatin for cisplatin or carboplatin may
optimize cytotoxicity when combined with gemcitabine. Two phase I trials of this
combination have been reported.[14]

The California Cancer Consortium is further evaluating this
combination with a fixed dose of oxaliplatin at 130 mg/m2 on day 1 and
escalating doses of gemcitabine on days 1 and 8 of a 21-day cycle (Table
4).
Laboratory correlative studies performed on patient tumor tissue are designed to
dissect potential molecular mechanisms of interaction, and include DNA repair
genes (ERCC1 and ribonucleotide reductase), deoxycitadine deaminase, HER2/neu,
apoptosis-related genes, and quantitation of oxaliplatin-DNA adducts in
peripheral blood mononuclear cells. A subsequent phase II trial of this
combination in advanced non-small-cell lung cancer is planned by the Southwest
Oncology Group.

Gemcitabine/cisplatin has proven to be one of the most
efficacious new combination chemotherapy regimens available for the treatment of
non-small-cell lung cancer. The platinum derivatives carboplatin and
oxaliplatin offer potential therapeutic advantages in terms of reduced
toxicities or possible increased efficacy. Further studies of gemcitabine in combination with platinum derivatives are clearly warranted.